Role of the Metabolite Noribogaine
J. Pablo, C.A. Kovera and D.C. Mash.
Department of Neurology, University of Miami School of Medicine,
Florida 33136, USA.
Ibogaine (IBO) a naturally occurring indole alkaloid derived from the roots of the rainforest shrub Tabernanthe iboga, has been demonstrated to have efficacy for the blockade of opiate withdrawal. However, it is likely that IBO’s purported efficacy may be due to the long-acting metabolite, because IBO has a rapid clearance from blood. IBO is O-demethylated to noribogaine (norIBO) in both animals and humans. We have obtained observational data on the effects of a single-dose administration of IBO on mood, craving and withdrawal symptoms in treatment-seeking patients with chemical dependency on opiates (N = 32). We observed significant reductions in negative health symptoms, as well as improvements in mood and energy/vigor for the post-ibogaine time points. Mean scores from category scales of the HCQ-NOW29 showed significantly reduced craving for opiates post treatment. Physician-rated assessments and subjective reports of opioid-dependent patient volunteers demonstrated an alleviation of withdrawal symptoms during detoxification with IBO. While these observations suggest treatment efficacy, the precise mechanism(s) accounting for these effects remain uncertain. Radioligand binding screens demonstrated that norIBO has affinity for the 5-HT transporter (SERT) and m- and k-opioid receptors. norIBO elevates extracellular levels of 5-HT and acts as a full m-agonist. Kinetic analysis of [3H]norIBO gave t1/2 values for biphasic dissociation with rapid and slow rate constants of 9.0 + 0.4 min and 3123.4 + 21.1 min (~2.2 days), respectively. Kinetic assays performed in the presence and absence of SERT occluders resulted in the loss of the fast dissociation rate, suggesting pseudoirreversible binding at a second target. The slow-rate of dissociation was blocked by the addition of a m-agonist. The multitarget actions of norIBO may explain how a single dose of IBO in humans blocks the opiate withdrawal syndrome.